Infections are a leading cause of morbidity and mortality for millions of older Americans. Emerging biologic and epidemiologic data suggest antimicrobial benefits from vitamin D supplements, and possibly marine omega-3 fatty acids (I-3 FA). However, large, long-term prevention trials with adequate dosing in general populations are not available. The IOM recently called for more research on vitamin D. We propose to take advantage of a large NIH-funded study - the VITamin D and OmegA-3 TriaL (VITAL) - to examine the short- and long-term effects of vitamin D and I-3 FA supplements on infection. We also will examine the effect of vitamin D on plasma levels of human cathelicidin antimicrobial peptide (hCAP18), a potential mechanism for the hypothesized antimicrobial benefits of vitamin D. VITAL is a randomized, double-blind, placebo-controlled, 2x2 factorial trial with 20,000 participants (men age e60y; women e65y). Starting in April 2011 and continuing through July 2012, subjects will be enrolled in a 3-month run-in, during which they will receive placebos. At the end of the run-in, those who remain willing and eligible, and who report having taken at least two-thirds of pills, will be randomly assigned to one of four groups for 5 years: vitamin D3 (2000 IU/d) and fish oil (EPA+DHA, 1 g/d); vitamin D3 and fish oil placebo; placebo vitamin D3 and fish oil; and placebo vitamin D3 and placebo fish oil. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects, and incidence of endpoints. Primary aims of this ancillary study will address upper respiratory infections (URIs) and require the timely creation of a subcohort (10% sample, n=2,000) in early 2012. This URI subcohort will receive special mailings in Feb/Mar 2012 (baseline), Oct/Nov 2012, and Feb/Mar 2013 (same season, 1 year later). The latter mailings will collect details about recent URIs (e.g., severity, duration of illness, treatments). We will collect baseline and 1-year follow-up blood specimens to test for changes in 25(OH)D, I-3, and hCAP18 levels. These data will answer several questions, including whether vitamin D increases hCAP18 levels, and whether this change mediates the hypothesized reduction in URIs. Secondary aims will examine several other types of infections (pneumonia & influenza, urinary tract infections, skin, any antimicrobial-treated infection, infection-related hospitalizations/sepsis), which we will confirm by CMS linkage. In a subset of 250 cases of each outcome, we will further confirm endpoints by supplemental questionnaire. Long-term follow-up will allow us to address the emerging concern that an early beneficial effect could be followed by a weakening or even reversal of benefit with prolonged supplementation. The current study presents a highly efficient and innovative strategy to evaluate vitamin D and I-3 FA supplementation for short- and long-term prevention of infectious diseases, and to test hCAP18 as a potential mechanism. The findings may have direct clinical and public health impact for the prevention of infections in older adults.